This proposal is based on the hypothesis that colorectal cancer (CRC) and other cancers principally occur in a high risk group that is defined by the carriage of specific genes that confer susceptibility to formation of adenomatous colon polyps. Additionally, identification of this group of individuals would lead to a cost effective strategy for reducing CRC mortality by targeting and screening those individuals who are at greatest risk. Genetic susceptibility for the development of CRC is well recognized. While the majority of colon and other cancers are sporadic, there is growing recognition that a significant proportion of cancer is due to inherited susceptibility. It is well established that germline mutations of some of the already known colon cancer susceptibility genes confer a marked risk of early onset colon neoplasia. The ultimate goal of this project is to test the prediction that susceptibility to colon polyp formation is determined by a major susceptibility allele. The goals of the study are (1) to develop a cohort of 300 adult sibling pairs who are concordant for either colon polyps and/or colon cancer; (2) to perform flexible signoidoscoppy on up to 600 siblings to determine the presence or absence of colon polyps; (3) to collect whole blood for DNA extraction, WBC storage, and serum storage; and (4) to develop polymorphic markers as a pilot project for a small number of candidate gene loci for colon polyp susceptibility.